Dioxaspiro derivatives



United States Patent This invention relates to novel dioxaspiroderivatives, and a process .for the manufacture thereof. Moreparticularly, this invention relates to dioxaspiro compounds of theformula:

wherein n represents either 1 or 2, and R, R R and R represent hydrogenor a lower alkyl radical from 1 to 3 carbon atoms. Those skilled in theart will appreciate that when n is 1 the product will be adioxaspirononane, and when n is 1 and 2 the product will be adioxaspirodecane and when n is 2 the product will be dioxaspiroundecane.

The products of this invention are prepared by the reduction of asuitable di-uns'aturated malonate with lithium aluminum hydride to givethe corresponding di-unsaturated 1,3-propanediol, followed bycyclization of the diol using catalytic amounts of a mineral acid togive the corresponding dioxaspiro derivative. For example, reduction ofdiethyl dimethallylmalonate with lithium aluminum hydride followed bycyclization of the 2,2-dimethallyl-1,3-propanediol gave the product3,3,8,8-tetramethyl-2,7 dioxaspiro( 4.4) nonane.

.On the other hand, a similar reduction of diethylmethallyl-3-methyl-2-butenyl)malonate followed by cyclization of the2-methally-l-2(3-methyl-2- butenyl)-1,3-propanediol gave3,3,8,8-tetramethyl 2,7 dioxaspiro(4.5) vdecane. Likewise, the abovementioned reaction sequence when applied to diethyl di(3-methyl-2-butenyl)malonate can give3,3,9,9-tetrarnethyl-2,8-dioxaspiro(5.5)undecane.

3,3,8-trimethyl-2,7-dioxaspiro(4.4)nonane was prepared by treatment of2,2-dirnethyl-4-allyl-4-hydroxymethyltetrahydrofuran heated on the steambath in the presence of 10% (by weight) concentrated hydrochloric acid.These conditions were also effective in the ring closure of'2-allyl-2-methallyl-1,3-propanediol to give the same product.

The compounds to which the invention relates are useful because of theirvaluable pharmacological properties. Thus, for example, they exhibitanti-.convulsant properties when tested by audiogenic seizures using astrain of susceptible mice. For example, it has been found that theanti-convulsant dose of 3,3,8-trimethyl- 2,7-dioxaspiro(4.4)nonane issubstantially lower than the lethal dose, and that the LD is 340 rug/kg.and that the anti-convulsant D is 75 mgJkg.

EXAMPLE 1 3,3,8,8-Tetramethyl-2,7Di0xaspiro(4.4 N onane (a) A solutionof 214.5 g. of diethyl dimethallylmalonate in 500 ml. of anhydrous ethylether was added dropwise over a 4 hour period to a vigorously stirredmixture of 45.6 -g. of lithium aluminum hydride and 1250 ml. ofanhydrous ethyl ether maintained at 5-20 C. The reaction mixture wasstirred for 2 hours. The mixture was cooled, and decomposed bysuccessive addition of methanol-ethyl ether, methanol-water, and water.The

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solids were triturated several times with ethyl ether and the combinedethereal extracts were washed with water and evaporated to dryness togive an oily product. Distillation of this oil afforded 136.5 g. of2,2-dimethallyl- 1,3-propanediol, B.P. 162.5l72.0 C./15-20 mm. Infrared:7\ max. 3.0 (hydroxyl), 3.25, 6.1 (unsaturation), 9.6-9.8 (hydroxyl),1125 (methallyl).

(b) 2,2-dimethally-l-1,3-propanediol (83.9 g.) was dissolved in 59.5 ml.of tetrahydrofuran and treated with 1.9 ml. of concentrated hydrochloricacid. The internal temperature of the solution rose spontaneously to 60C. and was cooled briefly, left 1 hour at room temperature, and refluxedfor a period of two hours. The tetrahydrofuran was removed bydistillation. The residue was dissolved in ethyl ether, washed withsmall amounts of dilute alkali to remove any acid, washed with water,dried, and evaporated to give 73.7 g. of a pale yellow liquid.Distillation of this product afforded 68.3 g. of3,3,8,8-tetramethyl-2,7-dioxaspiro(4.4)nonane, B.P. 115- 121 C./21 Ananalytical sample of 3,3,8,8-tetramethyl-2,7 dioxaspiro(4.4)nonane wasobtained by redistillat-ion through a. spinning band column having B.P.109110 C./3=0-31 mm, n 1.4 404. Another specimen had a B.P. of 207.5208C./760 rnrn.

Analysis.Calc. for C I-1 0 C, 71.69; H, 10.94. Found: C, 72.05, 72.13;H, 11.43, 11.19.

The infrared spectrum of 3,3,8,8-tetramethyl-2,7-dioxaspir0(4.4)nonaneindicated the absence of unsaturation and of hydroxyl groups and theappearance of an additional band in the methyl region.

EXAMPLE 2 3,3,8-Trimethyl-2J-Di0xaspir0(4.4)Nonane 2,2-dimethyl 4allyl-4hydroxymethyltetrahydrofuran (25 g.) was treated dropwise with6.5 ml. of concentrated hydrochloric acid. The internal temperature ofthe solution rose from 25 C. to 35 C. accompanied by faintdiscoloration. The solution was left 30 minutes at room temperature andthen warmed overnight on a steam bath. Concentrated sodium hydroxide(containing 4 g. of sodium hydroxide) was added to the solutionmaintained at 1525 C. and the mixture was extracted with ethyl ether.The ethereal solution was washed with water and the ether distilled togive 23 g. of a liquid. This liquid was distilled to afford 20.8 g. of3,3,8-trimethyl-2,7-dioxaspiro(4.4)nonane, B.P. 68-74 C./68 mm., 111.4439. The analytical specimen obtained by iiractional distillation ona spinning band column had B.P. 70.5- 71.0 C./6 mm., 11 1.4436.

Analysis.Calc. for C H gO z C, 70.55; H, 10.66. Found: C, 70.29; H,10.64.

The infrared spectrum of 3,3,8-trimethyl-2,7-dioxaspiro (4.4)nonaneshowed the appearance of a second band in the methyl region and thedisappearance of bands associated with unsaturation and hydroxyl groups,

EXAMPLE 3 3 ,3 ,8 -T rimethyl-Z,7-Di0xaspir0( 4 .4 N onane2-allyl-2-methallyl-1,3-propanediol (25 g.) was treated at roomtemperature with 6.5 m1. of concentrated hydrochloric acid. The internaltemperature rose rapidly and reached C. even with external cooling. Thematerial was warmed 7 hours on the steam bath, made basic by theaddition of 6 N sodium hydroxide, and extracted with ethyl ether. Theether was removed and the residue distilled to give 20.2 g. of3,3,8-trimethyl2,7-dioxaspiro (4.4)-nonane, B.P. 77-83 C./810 mm., r11.4438. The infrared spectrum of this product was identical withinexperimental error with that of the product from Example 2.

3 EXAMPLE 4 3,3 ,8,8-T etramethyl-2,7-D ioxaspiro (4 .5 Decane (a)Diethyl methallylmalonate (110.2 g.) was added during 5-10 minutes to asolution of sodium ethoxide (from 11.9 g. of sodium in 300 ml. ofethanol). The mixture was stirred for 30 minutes and 76.7 g. of3-methyl- Z-butenyl bromide was added during 20 minutes of stirring. Themixture was refluxed overnight, cooled to room temperature, and treatedwith water to dissolve the sodium chloride. The solution was slightlyacidic. The ethanol was removed in vacuo and the residual mixtureextracted with ethyl ether. The combined ethereal extracts were washedsparingly with water and the ether evaporated to give 139.2 g. of oilyproduct. Distillation of this product afforded 14 g. of forenm, B.P.72-123 C./11 mm., n 1.4495; 121.8 g. of diethyl methallyl(3-methyl-2-butenyl)-malonate, B.P. 121-162 C./11 mm., n 1.4566: and 1.8 g.of residue. Further distillation aflorded an analytical specimen ofdiethyl methallyl(3- methyl-Z-butenyl)malonate, B.P. 149-150 C./14 mm.,11 1.4571.

Analysis.-Calc. for 0 1-1 0 C, 68.05: H, 9.28. Found: C, 67.67, H, 9.14.

Infrared: max. 3.25 (unsaturation), 5.75 (carbonyl), 6.1 (unsaturation),7.25-7.32 (methyl), 8.3-8.5 (ester) and 11.15,. (methallyl). Byproceeding in a similar manner diethyl(3-methyl-2-butenyl)-malonatewould give diethyl di-(3-methyl-2-butenyl)malonate.

(b) Diethyl methallyl(3-methyl-2-butenyl)malonate (99.1 g.) wasdissolvedin 300 ml. of anhydrous ethyl ether and then added dropwiseduring 2 hours to 20 g. of lithium aluminum hydride slurried in 500 ml.anhydrous ethyl ether maintained at -20 C. The mixture was stirredduring 1 hour with the temperature rising to 25 C. and left at roomtemperature overnight. The mixture Was cooled With an ice-salt bath anddecomposed by the successive addition of methanol-ethyl ether,methanolwater, and water. 'Ihe solids were collected, washed repeatedlywith ether, the ethereal extracts combined, washed, and evaporated togive 67.3 g. of an oil. Distillation of this oil at 148-165 C./9 mm.afforded 65.6 g. of semipure 2-methallyl-2-(3-methyl-2-butenyl)-1,3-propanediol. The distillate upon standing crystallized with evolution ofheat afiording white needles, M.P. 54.5- 55.0 C.

Analysis.-Calc. for C H O C, 72.68, H, 11.18. Found: C, 72.74, H, 11.22.

Infrared: max. 3.0 (hydroxyl), 3.22, 6.1 (unsaturation), 6.9 (CH2), 7.25(methyl), 9.5-9.8 (hydroxyl), 11.25, (methallyl). By proceeding in asimilar manner diethyl di-(3-methyl-2-butenyl)malonate would give 2,2-di-'(3-methyl-2-bu-tenyl) -1,3-propanediol.

(c) 2-methallyl-2-( 3-methyl-2-butenyl -1, 3-propauediol (30 g.) in ml.of tetrahydrofuran was treated dropwise during 15 minutes With 28 ml. 6N hydrochloric acid accompanied by stirring. The internal temperature ofthe solution rose from 22 to 33 C. The solution was refluxed for 3 hoursand the tetrahydrofuran distilled at atmospheric pressure to give 31.9g. of crude 3,3,8,8-tetramethyl-2,7-dioxaspiro(4.5)decane. Distillationof this material through a spinning-band column afiorded an analyticalsample of 3,3,8,8-tetramethyl-2,7-dioxaspiro'(4.5) decane, B.P.94.0-94.5 C./6 mm., 11 1.4505.

Analysis.-Calc. for C H O C, 72.68, H, 11.18. Found: C, 72.66, 72.72, H,11.14, 11.24.

The infrared spectrum indicated the absence of unsaturation and hydroxylgroups and the presence of methyl groups (7.25, 7.35 1). By proceedingin a similar manner 2,2-di-(.3-methyl-2-butenyl)-1,3-propanediol wouldgive 3 ,3,9,9-tetramethyl-2,8-dioxaspiro (5.5 undecane.

What we claim is:

. 3,3,8,S-tetramethyl-2,7-dioxaspiro(4.4)nonane.

. 3,3 ,8-trimetl1yl-2,7-dioxaspiro 4.4) nonane.

. 3,3, 8,S-tetramethyl-2,7-dioxaspiro(4.5 decane.

. 3,3,9,9-tetramethyl-2,8-dioxaspiro(5.5)undecane,

from 1 to 3 carbon atoms, at least one of R, R R and R is alkyl and n isa positive integer from 1 to 2.

References Cited in the file of this patent Patterson et al.: The RingIndex, 2nd ed., pp. 134 and 222, Amer. Chem. Soc. (1960), QD 291.P3.

Chemical Abstracts, 5th Decennial Index, vols. 41-50, subject index,Cy-Ey, pp. 4230s-4231s (1947-1956), QD 1.A51.

